tbuckley/cabot-search huggingface dataset:
PB2153: SURGICAL SPECIMENS OF INDOLENT AND AGGRESSIVE B-NHLS SHOW DIFFERENCES IN THEIR FLOW-CYTOMETRY PROFILE OF PLOIDY, PROLIFERATING FRACTION AND PROPORTION OF TUMOR-ASSOCIATED MYELOID AND T-CELL SUBSETS
Authors: D. Azoulay, T. Tapuchi, H. I. Cohen, L. Akria, G. Stemer, O. Ronen
Journal: HemaSphere (2022)

Background: Multiparameter flow cytometry (FC) is an important and valuable diagnostic tool for specimens collected via minimally invasive techniques, when only a limited tissue sample is available and tissue architecture is inadequate. Aims: Here we examined and compared the incidence of various cellular components in specimens of patients with aggressive versus indolent B-cell non-Hodgkin’s lymphomas (B-NHLs). Methods: The data were retrospectively collected from surgical specimens collected via fine-needle aspiration or core biopsies that were submitted to our FC laboratory for a routine lymphoma diagnostic workup. The data included: ploidy status and incidences of cells in the proliferative fraction, lymphocytes, CD64+ monocytes, immature (iGr) and mature granulocytes (mGr) in the total CD45+ cellular component, clonal B cells, CD3+ T cells, CD3/CD56+ NK cells in the total lymphocyte population, CD4+ T cells, CD8+ T cells, CD4+/CD8+ DP T cells, CD4-/CD8- DN T cells and CD3+/CD56+ NKT cells in the total T cell component. Pearson Chi-squared or two-sided t test analysis was performed to compare the profiles of specimens of patients with aggressive versus indolent B-NHLs as determined by histopathological analysis. Results: A total of 40 specimens were included in this study (F:M [%] 62.5:37.5, age [mean ± SD, range] 67.87 ± 14.73 years, 27.4-92.6). Histopathological analysis confirmed the diagnosis of aggressive B-NHL in 23 (20 DLBCL, 2 MCL and 1 ALC) (57.5%) specimens, and indolent B-NHL in 17 (11 FL, 6 MZL) (42.5%) specimens. Specimens from aggressive B-NHLs showed an increased rate of aneuploidy (56.52% vs. 11.76% prob>chiSq=0.0025), increased incidences of cells in the proliferative fraction ([mean % ± SD] 13.03 ± 10.52 vs. 3.21 ± 1.42 p = 0.0005), CD64+ monocytes (3.89 ± 3.88 vs. 0.93 ± 0.75 p = 0.0038), iGr (4.43 ± 4.47 vs. 0.96 ± 0.86 p = 0.0033), CD8+ T cells (33.16 ± 16.23 vs. 18.54 ± 6.44 p = 0.001), DN T cells (6.90 ± 4.34 vs. 3.47 ± 1.74 p = 0.004) and DP T cells (6.74 ± 5.94 vs. 2.38 ± 1.26 p = 0.005), and reduced incidences of lymphocytes (72.71 ± 24.26 vs. 89.22 ± 13.33 p = 0.016), CD4+ and T cells (65.67 ± 15.86 vs. 78.68 ± 7.24 p = 0.003), as compared to specimens of indolent B-NHLs. Summary/Conclusion: These preliminary data confirm our previous report and suggest the proliferating fraction and the incidences of tumor-associated myeloid cells and T cells as flow cytometry-identifiable biomarkers that could assist in the differentiation between aggressive vs. indolent B-NHLs in specimens collected via minimally invasive sampling.
Detection of G Protein–Coupled Receptor Autoantibodies in Postural Orthostatic Tachycardia Syndrome Using Standard Methodology
Authors: Juliette Hall, Kate M. Bourne, Steven Vernino, Viktor Hamrefors, Isabella Kharraziha, Jan Nilsson, Robert S. Sheldon, Artur Fedorowski, Satish R. Raj
Journal: Circulation (2022)

Background: Postural orthostatic tachycardia syndrome (POTS) is a disorder of orthostatic intolerance that primarily affects women of childbearing age. The underlying pathophysiology of POTS is not fully understood, but it has been suggested that autoimmunity may play a role. The aim of this study was to compare concentrations of autoantibodies to cardiovascular G protein–coupled receptors between patients with POTS and healthy controls. Methods: Sera were collected from 116 patients with POTS (91% female; medium age, 29 years) and 81 healthy controls (84% female; medium age, 27 years) from Calgary, Canada, and Malmö, Sweden. Samples were evaluated for autoantibodies to 11 receptors (adrenergic, muscarinic, angiotensin II, and endothelin) using a commercially available enzyme-linked immunosorbent assay. Results: Autoantibody concentrations against all of the receptors tested were not significantly different between controls and patients with POTS. The majority of patients with POTS (98.3%) and all controls (100%) had α1 adrenergic receptor autoantibody concentrations above the seropositive threshold provided by the manufacturer (7 units/mL). The proportion of patients with POTS versus healthy controls who fell above the diagnostic thresholds was not different for any tested autoantibodies. Receiver operating characteristic curves showed a poor ability to discriminate between patients with POTS and controls. Conclusions: Patients with POTS and healthy controls do not differ in their enzyme-linked immunosorbent assay–derived autoantibody concentrations to cardiovascular G protein–coupled receptors. These findings suggest that these tests are not useful for establishing the role of autoimmunity in POTS.
Lymph node fibroblastic reticular cells preserve a tolerogenic niche in allograft transplantation through laminin α4
Authors: Lushen Li, Marina W. Shirkey, Tianshu Zhang, Wenji Piao, Xiaofei Li, Jing Zhao, Zhongcheng Mei, Yizhan Guo, Vikas Saxena, Allison Kensiski, Samuel J. Gavzy, Yang Song, Bing Ma, Jing Wu, Yanbao Xiong, Long Wu, Xiaoxuan Fan, Holly Roussey, Meng Li, Alexæander S. Krupnick, Reza Abdi, Jonathan S. Bromberg
Journal: Journal of Clinical Investigation (2022)

Lymph node (LN) fibroblastic reticular cells (FRCs) define LN niches and regulate lymphocyte homeostasis through producing diverse extracellular matrix (ECM) components. We examined the role of ECM laminin α4 (Lama4) using FRC-Lama4 conditional KO Pdgfrb-Cre-/- × Lama4fl/fl mice. Single-cell RNA-sequencing (scRNA-Seq) data showed the promoter gene Pdgfrb was exclusively expressed in FRCs. Depleting FRC-Lama4 reduced Tregs and dendritic cells, decreased high endothelial venules, impaired the conduit system, and downregulated T cell survival factors in LNs. FRC-Lama4 depletion impaired the homing of lymphocytes to LNs in homeostasis and after allografting. Alloantigen-specific T cells proliferated, were activated to greater degrees in LNs lacking FRC-Lama4, and were more prone to differentiate into effector phenotypes relative to the Treg phenotype. In murine cardiac transplantation, tolerogenic immunosuppression was not effective in FRC-Lama4 recipients, which produced more alloantibodies than WT. After lung transplantation, FRC-Lama4-KO mice had more severe graft rejection with fewer Tregs in their LNs. Overall, FRC-Lama4 critically contributes to a tolerogenic LN niche by supporting T cell migration, constraining T cell activation and proliferation, and promoting Treg differentiation. Hence, it serves as a therapeutic target for immunoengineering.
Association of environmental and socioeconomic indicators with serious mental illness diagnoses identified from general practitioner practice data in England: A spatial Bayesian modelling study
Authors: Joana Cruz, Guangquan Li, Maria Jose Aragon, Peter A. Coventry, Rowena Jacobs, Stephanie L. Prady, Piran C. L. White
Journal: PLoS Medicine (2022)

The evidence is sparse regarding the associations between serious mental illnesses (SMIs) prevalence and environmental factors in adulthood as well as the geographic distribution and variability of these associations. In this study, we evaluated the association between availability and proximity of green and blue space with SMI prevalence in England as a whole and in its major conurbations (Greater London, Birmingham, Liverpool and Manchester, Leeds, and Newcastle).
Lymphocytes in the neighborhood: good or bad for the kidney?
Authors: Hao Li, Maria G. Tsokos, George C. Tsokos
Journal: Journal of Clinical Investigation (2022)

Lupus nephritis (LN) is common in people with systemic lupus erythematosus (SLE) and advances, almost invariably, to end-stage renal disease (ESRD). In this issue of the JCI, Abraham, Durkee, et al. presented a large-scale immune cell landscape of kidney biopsies from patients with LN by combining multiplexed confocal microscopy imaging with customized computer vision and quantification. The presence of diverse CD4– T cells in small neighborhoods, but not of B cells or CD4+ T cells in large neighborhoods, is linked to the development of ESRD. Unexpectedly, B cells in the kidney heralded a good prognosis. The precise location of different types of immune cells allows inference on possible interactions between different immune cells and also between immune and kidney-resident cells. The data have important implications on the development of prognostic tools and effective targeted therapies in patients with LN.
Clinical observation of different doses of rituximab for the treatment of severe pemphigus: A single-center prospective cohort study
Authors: Jiao Zhang, Xueyi Huang, Zeqiao Zhang, Peizhen Zhao, Wenjing Chen, Yunsheng Liang, Hongfang Liu, Zemin Zhong, Yongfeng Chen
Journal: Journal of the American Academy of Dermatology (2022)
Experiences of Transgender and Gender Expansive Physicians
Authors: Lauren M. Westafer, Caroline E. Freiermuth, Michelle D. Lall, Sarah J. Muder, Eleanor L. Ragone, Angela F. Jarman
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Although LGBTQIA+ (lesbian, gay, bisexual, transgender, queer, and other sexual and gender minority) physicians experience bias in the workplace, there is a paucity of data on the experiences of physicians who identify specifically as transgender and/or gender expansive (TGE;<i>gender expansive </i>is an umbrella term encompassing individuals and gender identities that may exist beyond the binary framework [eg, may include nonbinary, genderqueer, and agender individuals]). <h3>Objectives</h3> To explore the professional experiences of TGE physicians, identify barriers to inclusion, and highlight stakeholder-derived strategies that promote an inclusive workplace. <h3>Design, Setting, and Participants</h3> This qualitative study informed by semistructured interviews was conducted among 24 TGE physicians in the US from April 1 to December 31, 2021. The sample of TGE physicians was recruited using convenience and snowball sampling. Interviews were recorded and transcribed. Using thematic analysis, at least 2 members of the research team performed blinded coding of each transcript, in an iterative process. <h3>Main Outcomes and Measures</h3> Data collection and thematic analysis examining themes of physicians' experiences. <h3>Results</h3> Among 24 physicians (mean [SD] age, 39 [1.4] years) interviewed, 8 (33%) self-identified as transgender women, 7 (29%) as transgender men, 4 (17%) as nonbinary, 3 (13%) as transgender and nonbinary, and 2 (8%) as genderqueer. Prominent themes of the interviews included emotional distress as a result of transphobia, dominance of a rigid binary gender paradigm, and structural and institutional factors that are associated with psychological and physical safety and feelings of isolation as a TGE physician. Clear steps of affirmation were identified that could mitigate the emotional stressors, including signs of safety, active allyship, and mentorship by other TGE physicians. <h3>Conclusions and Relevance</h3> In this qualitative study, TGE physicians reported facing both overt and subtle biases associated with their identity and gender presentation. Participants also noted several interpersonal and structural factors that mitigate the effect of these biases.
IMM-BCP-01, a patient-derived anti–SARS-CoV-2 antibody cocktail, is active across variants of concern including Omicron BA.1 and BA.2
Authors: Pavel A. Nikitin, Jillian M. DiMuzio, John P. Dowling, Nirja B. Patel, Jamie L. Bingaman-Steele, Baron C. Heimbach, Noeleya Henriquez, Chris Nicolescu, Antonio Polley, Eden L. Sikorski, Raymond J. Howanski, Mitchell Nath, Halley Shukla, Suzanne M. Scheaffer, James P. Finn, Li-Fang Liang, Todd Smith, Nadia Storm, Lindsay G. A. McKay, Rebecca I. Johnson, Lauren E. Malsick, Anna N. Honko, Anthony Griffiths, Michael S. Diamond, Purnanand Sarma, Dennis H. Geising, Michael J. Morin, Matthew K. Robinson
Journal: Science Immunology (2022)

Monoclonal antibodies are an efficacious therapy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, rapid viral mutagenesis led to escape from most of these therapies, outlining the need for an antibody cocktail with a broad neutralizing potency. Using an unbiased interrogation of the memory B cell repertoire of patients with convalescent COVID-19, we identified human antibodies with broad antiviral activity in vitro and efficacy in vivo against all tested SARS-CoV-2 variants of concern, including Delta and Omicron BA.1 and BA.2. Here, we describe an antibody cocktail, IMM-BCP-01, that consists of three patient-derived broadly neutralizing antibodies directed at nonoverlapping surfaces on the SARS-CoV-2 Spike protein. Two antibodies, IMM20184 and IMM20190, directly blocked Spike binding to the ACE2 receptor. Binding of the third antibody, IMM20253, to its cryptic epitope on the outer surface of RBD altered the conformation of the Spike Trimer, promoting the release of Spike monomers. These antibodies decreased Omicron SARS-CoV-2 infection in the lungs of Syrian golden hamsters in vivo and potently induced antiviral effector response in vitro, including phagocytosis, ADCC, and complement pathway activation. Our preclinical data demonstrated that the three-antibody cocktail IMM-BCP-01 could be a promising means for preventing or treating infection of SARS-CoV-2 variants of concern, including Omicron BA.1 and BA.2, in susceptible individuals.
Cancer cell-autonomous overactivation of PARP1 compromises immunosurveillance in non-small cell lung cancer
Authors: Pan Juncheng, Adrien Joseph, Antoine Lafarge, Isabelle Martins, Florine Obrist, Jonathan Pol, Ester Saavedra, Sijing Li, Allan Sauvat, Giulia Cerrato, Sarah Lévesque, Marion Leduc, Oliver Kepp, Sylvère Durand, Fanny Aprahamian, Nitharsshini Nirmalathansan, Judith Michels, Guido Kroemer, Maria Castedo
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background High activity of poly(ADP-ribose) polymerase-1 (PARP1) in non-small cell lung cancer (NSCLC) cells leads to an increase in immunohistochemically detectable PAR, correlating with poor prognosis in patients with NSCLC, as well as reduced tumor infiltration by cytotoxic T lymphocytes (CTLs). Intrigued by this observation, we decided to determine whether PARP1 activity in NSCLC cells may cause an alteration of anticancer immunosurveillance. Methods Continuous culture of mouse NSCLC cells in the presence of cisplatin led to the generation of cisplatin-resistant PAR high clones. As compared with their parental controls, such PAR high cells formed tumors that were less infiltrated by CTLs when they were injected into immunocompetent mice, suggesting a causative link between high PARP1 activity and compromised immunosurveillance. To confirm this cause-and-effect relationship, we used CRISPR/Cas9 technology to knock out PARP1 in two PAR high NSCLC mouse cell lines (Lewis lung cancer [LLC] and tissue culture number one [TC1]), showing that the removal of PARP1 indeed restored cisplatin-induced cell death responses. Results PARP1 knockout (PARP1 KO ) cells became largely resistant to the PARP inhibitor niraparib, meaning that they exhibited less cell death induction, reduced DNA damage response, attenuated metabolic shifts and no induction of PD-L1 and MHC class-I molecules that may affect their immunogenicity. PAR high tumors implanted in mice responded to niraparib irrespective of the presence or absence of T lymphocytes, suggesting that cancer cell-autonomous effects of niraparib dominate over its possible immunomodulatory action. While PAR high NSCLC mouse cell lines proliferated similarly in immunocompetent and T cell-deficient mice, PARP1 KO cells were strongly affected by the presence of T cells. PARP1 KO LLC tumors grew more quickly in immunodeficient than in immunocompetent mice, and PARP1 KO TC1 cells could only form tumors in T cell-deficient mice, not in immunocompetent controls. Importantly, as compared with PAR high controls, the PARP1 KO LLC tumors exhibited signs of T cell activation in the immune infiltrate such as higher inducible costimulator (ICOS) expression and lower PD-1 expression on CTLs. Conclusions These results prove at the genetic level that PARP1 activity within malignant cells modulates the tumor microenvironment.
Characteristics associated with the residual risk of severe COVID-19 after a complete vaccination schedule: A cohort study of 28 million people in France
Authors: Laura Semenzato, Jérémie Botton, Jérôme Drouin, Bérangère Baricault, Marion Bertrand, Marie-Joëlle Jabagi, François Cuenot, Stéphane Le Vu, Rosemary Dray-Spira, Alain Weill, Mahmoud Zureik
Journal: The Lancet Regional Health - Europe (2022)

Prior to the availability of vaccines, the risk factors for developing severe forms of COVID-19 were mostly older age and various comorbidities such as diabetes, cardiovascular diseases, mental disorders, transplantations, and kidney disease. Although vaccines have been shown to be highly effective in preventing severe forms of COVID-19, a residual risk may persist, despite vaccination, for certain population groups.The study was based on data from the national COVID-19 vaccination database (VAC-SI) coupled with the National Health Data System (SNDS), which contains comprehensive reimbursement and hospitalisation data for all of France. All people fully vaccinated by July 31, 2021, with a double-injection vaccine, i.e., the mRNA BNT162b2, mRNA-1273, or ChAdOx1 nCoV-19 vaccines, or a single dose for people with a previous confirmed SARS-CoV-2 infection were included and followed until August 31, 2021. Cox proportional hazard models were performed to estimate adjusted hazard ratios (aHR) for COVID-19-related hospitalisation or in-hospital death associated with age, gender, deprivation index, comorbidities, and immunosuppressive or oral corticosteroid therapy from day 14 after full-vaccination.In a population of 28,031,641 fully vaccinated individuals with an average follow-up of 80 days, 5,345 (87 hospitalisations per 100,000 person-years) were hospitalised for COVID-19 and 996 (16 in-hospital death per 100,000 person-years) died in hospital. In multivariable analysis, a higher risk was observed with increasing age, male gender, and social deprivation. Most of the 47 chronic conditions considered were positively associated with an increased risk of COVID-19-related hospitalisation and a slight excess risk of death. The risk of hospitalisation and in-hospital death for COVID-19 also increased with the use of immunosuppressants (aHR 3.3 [2.8-3.8] and 2.4 [1.7-3.5], respectively) and oral corticosteroids (aHR 2.8 [2.5-3.1] and 4.1 [3.3-5.1]).Less than 10% (519/5,345) of hospitalised cases and 2% (24/996) of those who died in hospital had no identified comorbidities. There was a strong association between an increasing number of comorbidities and the risk of hospitalisation and in-hospital death (e.g., 5+ versus none, aHR 10.1 95%CI 9.0-11.5 and 17.8 95%CI 11.5-27.4, respectively).Although vaccination has dramatically reduced the occurrence of severe forms of COVID-19, a residual risk remains for the elderly, immunocompromised, and polypathological populations and warrants complementary preventive measures.None.
The Achilles’ heel of cancer survivors: fundamentals of accelerated cellular senescence
Authors: Shameel Shafqat, Evelyn Arana Chicas, Areez Shafqat, Shahrukh K. Hashmi
Journal: Journal of Clinical Investigation (2022)

Recent improvements in cancer treatment have increased the lifespan of pediatric and adult cancer survivors. However, cancer treatments accelerate aging in survivors, which manifests clinically as the premature onset of chronic diseases, such as endocrinopathies, osteoporosis, cardiac dysfunction, subsequent cancers, and geriatric syndromes of frailty, among others. Therefore, cancer treatment-induced early aging accounts for significant morbidity, mortality, and health expenditures among cancer survivors. One major mechanism driving this accelerated aging is cellular senescence; cancer treatments induce cellular senescence in tumor cells and in normal, nontumor tissue, thereby helping mediate the onset of several chronic diseases. Studies on clinical monitoring and therapeutic targeting of cellular senescence have made considerable progress in recent years. Large-scale clinical trials are currently evaluating senotherapeutic drugs, which inhibit or eliminate senescent cells to ameliorate cancer treatment-related aging. In this article, we survey the recent literature on phenotypes and mechanisms of aging in cancer survivors and provide an up-to-date review of the major preclinical and translational evidence on cellular senescence as a mechanism of accelerated aging in cancer survivors, as well as insight into the potential of senotherapeutic drugs. However, only with time will the clinical effect of senotherapies on cancer survivors be visible.
PB2138: VITALIZE TRIAL: A PHASE 2B, OPEN-LABEL, MULTICENTER, RANDOMIZED PARALLEL-GROUP, TWO-STAGE, STUDY OF MAVEROPEPIMUT-S, PEMBROLIZUMAB, WITH OR WITHOUT INTERMITTENT LOW-DOSE CYCLOPHOSPHAMIDE, IN R/R DLBLC
Authors: E. Lee, M. Matasar, R. Conlon, K. Mody, S. Fiset, J. Graff
Journal: HemaSphere (2022)

Background: Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma in adults, and up to 40% of patients will be refractory to front-line therapy or experience a relapse. In the relapsed/refractory (r/r) setting, novel treatment options are available, but many patients will relapse following or be ineligible for such treatment options, due in part to the safety profile. Thus, more effective, better tolerated therapeutic options are needed. Maveropepimut-S (MVP-S, previously DPX-Survivac) leverages the DPX platform, a non-aqueous, lipid-based delivery system, to educate a specific and persistent T cell-based immune response to 5 HLA-restricted peptides from survivin, a cancer-associated protein commonly upregulated in advanced, malignancies including DLBCL. In a prior clinical study in patients with r/r DLBCL (SPiReL: NCT03349450), MVP-S in combination with pembrolizumab and low dose, intermittent cyclophosphamide (CPA) led to durable complete and partial responses as well as persistent, survivin-specific T cells, particularly in patients with PD-L1+ disease. Importantly, this combination was well-tolerated. Aims: Further exploration of the regimen in r/r DLBCL is warranted to confirm and extend these encouraging results and to clarify the relative contributions of the constituent components of the combination regimen. Methods: The VITALIZE trial (NCT04920617) is a phase 2b, open-label, randomized trial of MVP-S and pembrolizumab, with or without intermittent low-dose CPA. Eligible patients with r/r DLBCL (including transformed indolent B cell lymphomas and high-grade lymphoma) have persistent or progressive disease following ≥ 2 lines of prior systemic therapy and are ineligible for, or have relapsed after, ASCT and/or CAR-T. Using a Simon’s Two-Stage Design, patients will be randomized (1:1) to: Arm 1: MVP-S, pembrolizumab and CPA or, Arm 2: MVP-S and pembrolizumab, and will be treated for up to 2 years. The primary objective of the study is centrally assessed objective response rate (ORR) (Lugano 2014), and secondary endpoints include PFS, DoR, DCR, OS and safety. Exploratory objectives include characterization of outcomes based on PD-L1 expression, and survivin-specific immunogenicity in baseline and on-treatment blood and tissue samples. This study will enroll up to 92 eligible subjects at 65 global study sites. Enrollment has begun, with one subject enrolled as of abstract submission date. Results: Trial in progress Image:Summary/Conclusion: Trial in progress